CN117597335A - Ring closure of benzoquinone containing unsaturated side chains Using basic catalyst - Google Patents

Ring closure of benzoquinone containing unsaturated side chains Using basic catalyst Download PDF

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CN117597335A
CN117597335A CN202280030782.6A CN202280030782A CN117597335A CN 117597335 A CN117597335 A CN 117597335A CN 202280030782 A CN202280030782 A CN 202280030782A CN 117597335 A CN117597335 A CN 117597335A
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carbon
formula
compound
independently
configuration
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维尔纳·邦拉蒂
沃夫·库恩滋
梅尔特姆·提尔潘奇
托马斯·涅斯切
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DSM IP Assets BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans

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Abstract

The present invention relates to the formation of compounds of formula (I) by ring closure of compounds of formula (II) in the presence of a catalytic amount of a base. This reaction has been found to be very efficient, for example providing an efficient route for the synthesis of 3, 4-dehydro-alpha-tocotrienol, alpha-tocotrienol and alpha-tocopherol, respectively.

Description

Ring closure of benzoquinone containing unsaturated side chains Using basic catalyst
Technical Field
The present invention relates to the field of synthesis of chromanes and chromenes, in particular synthesis of 3, 4-dehydrotocopherols, 3, 4-dehydrotocotrienols, tocopherols and tocotrienols.
Background
Vitamin E and its esters are an important class of chromane compounds. The chromane is synthesized by the corresponding chromene.
There are different pathways for the formation of chromenes.
Schudel, mayer, isler, helv.Chim. Acta 46,2517-2526 (1963) discloses the formation of 3, 4-dehydrotocotrienol by the ring closure reaction of geranyl-geranyltrimethylquinone during the formation of chromene by ring closure with pyridine as reaction medium, i.e. pyridine is present in large amounts (corresponding to a large excess relative to the amount of benzoquinone used). Since pyridine is a compound which is carcinogenic to animals and is also a highly flammable compound, its use is very disadvantageous, especially in the case of large quantities. Furthermore, the resulting reaction mixture is a complex mixture requiring complex derivatization to isolate the desired product, to form dehydrotocotrienol paraphenylazo benzoate for isolation, and to purify by crystallization. In this process, the very expensive and highly toxic chemical 4- (phenylazo) benzoyl chloride is used, so that the process as a whole is very disadvantageous.
There are alsoK.H. et al, chem.Ber.115,1278-1285 (1982) and Tershima K. et al, bioorganic&Medicinal Chemistry 10,1619, 1619-1625 (2002) discloses a cyclisation reaction of the corresponding benzoquinone in a large molar excess of pyridine under reflux.
WO 2015/028643 A1 discloses the intramolecular hydrogenation of chiral arylalkyne to form a chromene by Au (I) or Ag (I) catalysis. Gold and silver catalysts are very expensive.
Disclosure of Invention
Accordingly, the problem addressed by the present invention is to provide a process for providing chromenes and chromans which avoids the use of large amounts of pyridine or general bases.
This problem is solved by the method according to claim 1. It has been found in particular that in the ring closure of benzoquinone of formula (II) a catalytic amount of a base can be used to produce chromene of formula (I). In particular, strong basic catalysts have been found to be particularly suitable as catalytic bases for the above-described ring closure reactions. It has been found that the compounds of formula (I) can be obtained in very high conversions and yields.
This process provides a very advantageous synthetic route for chromanes of formula (III) or (IV) as claimed in claim 8 or 9.
Other aspects of the invention are subject matter of the other independent claims. Particularly preferred embodiments are the subject matter of the dependent claims.
Detailed Description
In a first aspect, the present invention relates to a process for the preparation of a compound of formula (I),
the process comprises a ring closure step of a compound of formula (II) in the presence of a basic catalyst, yielding a compound of formula (I)
The compound is used as a carrier of a compound,
wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl;
R 3 and R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z-configuration or E-configuration when attached to a carbon-carbon double bond,
characterized in that the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.
For clarity, some terms used herein are defined as follows:
herein, "C x-y Alkyl "means an alkyl group containing from x to y carbon atoms, e.g. C 1-3 Alkyl means an alkyl group containing 1 to 3 carbon atoms. The alkyl group may be straight or branched. For example, -CH (CH) 3 )-CH 2 -CH 3 Regarded as C 4 -an alkyl group.
In this context, if the same symbol or group label is present in multiple formulas, the definition of the group or symbol in a particular formula applies to other formulas containing the same label.
Herein, the term "independently of each other" means that in the context of substituents, molecules or groups, the same named substituents, molecules or groups may occur simultaneously in the same molecule in different meanings.
Herein, any dotted line in the formula represents a bond where a substituent is bound to the rest of the molecule.
Any of the formulae herein has a dashed lineIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond.
In any of the formulas herein, the wavy line represents a carbon-carbon bond, which is in the Z configuration or the E configuration when attached to a carbon-carbon double bond. In all molecules, the carbon-carbon double bond is preferably in the E configuration.
“pK a "negative base 10 logarithm (pka= -log), commonly referred to as the acid dissociation constant 10 K a ). When the organic acid has multiple protons, pK as used herein a Related to the dissociation constant of the last proton. For example, for a base having two basic sites, "pk a "AND pK a2 Related to the following. pK (pK) a Is measured at standard temperature and pressure.
A compound of formula (II)
The compounds of formula (II) are known to the person skilled in the art and their synthesis methods are also known.
In a preferred embodiment, the substituents R 3 And R is 4 Represents methoxy. In the present embodiment, any with broken linesPreferably represents a carbon-carbon double bond, most preferably in the E configuration.
Ubiquinone is an important representative of the present embodiment. Ubiquinone is represented by ubiquinone-2 (n=0), ubiquinone-3 (n=1), ubiquinone-4 (n=2), ubiquinone-5 (n=3), ubiquinone-6 (n=4), ubiquinone-7 (n=5), ubiquinone-8 (n=8), ubiquinone-9 (n=9), ubiquinone-4 (n=2), ubiquinone-5 (n=3), ubiquinone-6 (n=4), ubiquinone-7 (n=5), ubiquinone-8 (n=6), ubiquinone-9 (n=7) and ubiquinone-10 (n=8) according to the number of isoprenoid groups in the side chain. Ubiquinone is also known as the old coenzyme Q. Ubiquinone-10 (n=8) (=coenzyme q10) is a particularly preferred species in this embodiment.
In another preferred embodiment, the substituents R 3 And R is 4 Represents H or methyl. R is R 3 ＝R 4 ＝CH 3 Is preferred.
R is particularly preferred 1 ＝R 3 ＝R 4 ＝CH 3 。
Preferably n=2. It is further preferred that all of formula (II) bear a dashed lineIs a carbon-carbon double bond, preferably both in the E configuration.
In this embodiment, the compound of formula (II) is preferably a compound of formula (II-BB)
Geranylgeranyl trimethoquinone
In another preferred embodiment, the substituents R 3 And R is 4 Together represent-CH-and form an aromatic group. The compound of the present embodiment is expressed as
In the present embodiment, R 1 Preferably methyl.
Vitamin K1 (phylloquinone) is an example of this embodiment.
Menaquinones (MKs), also known as vitamin K2, are another important representative of this embodiment.
Any with broken linesPreferably represents a carbon-carbon double bond, preferably in the E configuration.
Depending on the number of isoprenoid groups in the side chain, menaquinones are denoted MK-2 (n=0), MK-3 (n=1), MK 4 (n=2), MK-5 (n=3), MK-6 (n=4), MK-7 (n=5), MK-8 (n=6), MK-9 (n=7), MK-10 (n=8), MK-11 (n=9), MK-12 (n=10) and MK-13 (n=11).
MK-4 (n=2) is a particularly preferred species in this embodiment.
If any with broken linesAnd (2) represents a carbon-carbon double bond, those skilled in the art would expect to be at risk of forming a secondary ring (through the existing carbon-carbon double bond). Since this is not observed, it is particularly preferred that at least one bond with a broken line is a carbon-carbon double bond. Thus, this methodIn particular, alpha-tocotrienols having three double bonds in the side chains can be obtained. Alpha-tocotrienol is an important compound in natural vitamin E.
Basic catalyst
The process comprises a ring closure step of the compound of formula (I) in the presence of a basic catalyst ("cat") to produce the compound of formula (I) as shown in step a) of the reaction scheme of fig. 1.
The basic catalyst is preferably an alkali metal or alkaline earth metal hydroxide or carbonate, in particular an alkali metal hydroxide.
Furthermore, it is preferred that the basic catalyst is an organic amine, in particular an organic tertiary amine.
The basic catalyst is a base. Not all bases are equally effective in the present invention. Preferably the basic catalyst is not pyridine. It has been proved that the conjugate acid of the basic catalyst has a pK measured in water a Values between 8.6 and 15.7, in particular between 9 and 15.7, are particularly suitable. This means that the basic catalyst has a pK of b The value is preferably between 5.4 and 0, in particular between 5 and 0.
Pk of the corresponding acid a Several examples of (a) are:
alkali pka 1
1, 5-diazabicyclo [4.3.0]Non-5-ene (=dbn) 13.42 3
1, 8-diazabicyclo [5.4.0]Undec-7-ene (=dbu) 12 2 ,13.28 3
1-azabicyclo [2.2.2]Octane (=quinuclidine) 11 2 ,10.95 3
4- (dimethylamino) pyridine (=dmap) 9.2 2 ,9.7 3
Cytisine (sparteine) 9.45 2
1, 4-diazabicyclo [2.2.2]Octane (=dabco) 8.8 2 ,8.82 3
NaOH 15.7 2
Na 2 CO 3 10.4 3
Morpholine (III) 4 8.36 2 ,8.49 3
Triethanolamine salt 4 7.76 3
Pyridine compound 4 5.23 2 ,5.23 3
1 Pka of the corresponding conjugate acid
2 H.Ripin；D.A.Evans(2002)."pK a 's of Nitrogen Acids"
https://organicchemistrydata.org/hansreich/resources/pka/pka_data/ evans_pKa_table.pdf
3 https://www.aatbio.com/data-sets/pka-and-pkb-reference-table
4 Less preferred basic catalysts (pk a <8.6)
In one embodiment, the basic catalyst is an organic amine, in particular selected from the group consisting of: 4-dimethylaminopyridine (=dmap), 1, 8-diazabicyclo [5.4.0] undec-7-ene (=dbu), 1, 5-diazabicyclo [4.3.0] non-5-ene (=dbn), 1, 4-diazabicyclo [2.2.2] octane (=dabco), 1-azabicyclo [2.2.2] octane (=quinuclidine) and sparteine (sparteine), preferably selected from the group consisting of 4-dimethylaminopyridine (=dmap), 1, 8-diazabicyclo [5.4.0] undec-7-ene (=dbu) and 1-azabicyclo [2.2.2] octane (=quinuclidine).
In another embodiment, the basic catalyst is preferably an alkali metal or alkaline earth metal hydroxide or carbonate, preferably an alkali metal or alkaline earth metal hydroxide, in particular an alkali metal hydroxide. In this embodiment, the most preferred basic catalyst is NaOH or KOH.
The base cannot in particular be a hydride, such as sodium hydride, because molecular hydrogen is formed when the hydride is contacted with a compound of formula (II). The formation of hydrogen can create significant safety hazards during the closed loop step and general processing.
When the base is used in solid form, preference is given to using phase transfer agents, in particular quaternary ammonium salts, in particular of the formula [ NR ] 4 ]Quaternary ammonium salts of X, wherein R is C 2-18 Alkyl, in particular C 3-8 -alkyl, X is a halide. Preferably the phase transfer agent is tetrabutylammonium halide, in particular tetrabutylammonium bromide. The phase transfer agent is preferably used in an amount of 0.1 to 10mol%, in particular 0.5 to 2mol%, relative to the compound of formula (II).
If the basic catalyst is an alkali metal hydroxide, in another embodiment, water may also be present.
The ring closure step is preferably carried out in a hydrocarbon solvent, in particular toluene.
In case a hydrocarbon solvent is used, the solvent is preferably used in an amount such that the solution with the compound of formula (II) is between 0.05 and 5 moles, more preferably between 0.1 and 1 mole, with respect to the compound of formula (II).
In the presence of water, it is preferred that the ring closure reaction is carried out in a two-phase system, i.e. an aqueous phase and an organic phase, in particular with an aqueous phase and an organic solvent phase.
Emphasis is placed on: alkaline substanceCatalytic reactionIn amounts, i.e. basic catalysts relative to the compounds of formula (II)Not beIs present in stoichiometric amounts, but in significantly lower amounts, i.e. the molar ratio of basic catalyst to compound of formula (I) is preferably from 1:1'000 to 1:5, in particular from 1:100 to 1:10.
The closed loop step is generally carried out with stirring, preferably at a temperature between 40 and 200 ℃, preferably between 90 and 150 ℃, more preferably at the reflux temperature of the organic solvent if an organic solvent is used, and/or at a pressure between 1 and 10 bara. Furthermore, the reaction is preferably carried out under an inert atmosphere, preferably under nitrogen.
The above process has been shown to produce compounds of formula (I) successfully.
In particular, the above-described process allows the desired compound of formula (I) to be isolated simply, i.e. without any complicated derivatization, and subsequent purification by crystallization and final chemical conversion of the derivative to the desired compound, as is not required, for example, by the process disclosed in Schudel, mayer, isler, helv.Chim. Acta 46,2517-2526 (1963).
Particularly preferred embodiments of the compounds of formula (I) are compounds of formulae (I-A), (I-B) and (I-C), preferably compounds of formulae (I-AA), (I-BB), (I-CC 1) and (I-CC 2):
n=0-9, in particular n=8
n=0-9, in particular n=8
n=0-9, in particular n=2
n＝0-12
n=0-12, in particular n=2
Highly preferred compounds are of formula (I-As).
n=3-9, in particular n=8.
Highly preferred compounds are of formula (I-Cis),
n=1-12, in particular n=2-5.
The compounds of formula (I) obtained as described above may be hydrogenated by means of a hydrogenating agent.
In one embodiment, only the carbon-carbon double bonds in the ring are hydrogenated while the olefinic carbon-carbon double bonds are not hydrogenated ("partially hydrogenated") upon hydrogenation, thus providing a compound of formula (III), as shown in fig. 1.
Particularly preferred embodiments of the compounds of formula (III) are compounds of formulae (III-A), (III-B) and (III-C), preferably compounds of formulae (III-AA), (III-BB), (III-CC 1) and (III-CC 2):
n=0-9, in particular n=8
n=0-9, in particular n=8
n=0-9, in particular n=2
n＝0-12
n=0-12, in particular n=2
Highly preferred compounds are of formula (III-Cis),
n=3-6, in particular n=5.
In another embodiment, in this hydrogenation reaction, all of the olefinic carbon-carbon double bonds are hydrogenated ("fully hydrogenated") to give compounds of formula (IV), as shown in fig. 1.
Particularly preferred embodiments of the compounds of formulSup>A (IV) are compounds of formulae (IV-A), (IV-B) and (IV-C), preferably compounds of formulae (IV-A), (IV-BB) and (IV-CC):
n=0-9, in particular n=8
n=0-9, in particular n=2
n＝0-12
Highly preferred compounds are of formula (IV-Cs),
n=3-12, in particular n=3-5.
Thus, in a further aspect, the present invention also relates to a process for the preparation of a compound of formula (III),
the method comprises the following steps:
a) Preparing a compound of formula (I) by a process as detailed above;
any of which is provided with a dotted lineIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond;
b) The compounds of formula (I) are partially hydrogenated by means of a hydrogenating agent suitable for partial hydrogenation to give compounds of formula (III).
The hydrogenating agent used in step b) is a hydrogenating agent which hydrogenates only the carbon-carbon double bonds of the ring of formula (I). Particularly suitable for use as hydrogenating agents are sodium/ethanol, as described in Schudel, mayer, isler, helv. Chim. Acta 46,2517-2526 (1963), in particular on page 2524, last paragraph.
Thus, in a further aspect, the present invention also relates to a process for the preparation of a compound of formula (IV),
the method comprises the following steps:
a) Preparing a compound of formula (I) by a process as detailed above;
any of which is provided with a dotted lineIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond;
b') hydrogenating the compound of the formula (I) with the aid of a hydrogenating agent to give the compound of the formula (IV).
The hydrogenating agent used in step b') is a hydrogenating agent which is capable of hydrogenating all olefinic carbon-carbon double bonds in the ring of the formula (I). Particularly suitable as hydrogenation agent is hydrogen in the presence of a group 7,8, 9 or 10 transition metal, in particular selected from the group consisting of Pd, pt, rh, ru, mn, fe, co and Ni, more preferably Pd.
The heterogeneous transition metal catalyst is preferably a heterogeneous supported transition metal catalyst.
In this embodiment, the transition metal is supported on a carrier, i.e., palladium is attached to and/or deposited on the carrier. The carrier is a solid material.
The support is preferably a carbon or inorganic support. Preferred inorganic supports are oxides or carbonates. The preferred oxides are Si, al, ce, ti or Zr oxides, in particular Al or Si oxides. Particularly preferred are silica, alumina, titania and ceria.
If the support is Ce, the preferred oxide is CeO 2 . Preferably, the oxide of Al is Al 2 O 3 And AlO (OH). Particularly preferred is Al 2 O 3 。
Preferably the hydrogenation is carried out under pressure, in particular under a hydrogen pressure of from 2 to 20 bar. Further preferably, the hydrogenation is carried out at a temperature of from 0 ℃ to 100 ℃.
The compositions comprising the compounds of formula (II) and the basic catalyst itself are also an object of the invention.
Thus, in another aspect, the invention relates to a composition comprising:
i) A compound of formula (II)
Wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl;
R 3 and R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond;
and
Any wavy lines represent carbon-carbon bonds independently of each other and when attached to carbon-carbon double bonds
In the Z or E configuration;
and
ii) a basic catalyst;
characterized in that the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.
The compounds of formula (II) and the basic catalyst and preferred embodiments thereof have been discussed in detail above with respect to the process.
In the present invention, catalytic amounts of base have been found to be useful in the effective ring closure in the ring closure step described above.
Thus, in a further aspect, the present invention relates to the catalytic use of a base for the ring closure reaction of a compound of formula (II) to produce a compound of formula (I),
wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl
R 3 And R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when attached to a carbon-carbon double bond.
The compounds of formula (II), base catalysts and ring closure steps and preferred embodiments thereof have been discussed in detail above for the process.
It has further been found that compounds of the formulSup>A (I-A) or (I-C) or (III-A) or (III-C) or (IV-A) or (IV-C) have an antioxidant property.
Thus, in Sup>A further aspect, the invention relates to the use of Sup>A compound of formulSup>A (I-A) or (I-C) or (III-A) or (III-C) or (IV-A) or (IV-C) as an antioxidant,
wherein n=0-9, in particular n=8
Wherein n=0 to 12
Wherein n=0-9, in particular n=8
Wherein n=0 to 12
Wherein n=0-9, in particular n=8
n＝0-12
Wherein the method comprises the steps of
R 1 Represents hydrogen or methyl.
The compounds of formulSup>A (I-A) or (I-C) or (III-A) or (III-C) or (IV-A) or (IV-C) and their preferred embodiments have been discussed in detail above for the process.
Several of the compounds disclosed herein are novel. These compounds are not only novel, but also inventive, as they are suitable for use in the disclosed methods and uses.
Thus, in a further aspect, the invention relates in particular to compounds of the formula (I-As) or (I-Cis) or (III-Cis) or (IV-Cs),
wherein n=3-9, in particular n=8
Wherein n=1-12, in particular n=2-5;
wherein n=3-6, in particular n=5;
where n=3-12, in particular n=3-5.
And wherein
R 1 Represents hydrogen or methyl;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond.
Examples
The following experiments further illustrate the invention.
(E) Formation of (E) -2- (4, 8-dimethylnon-3, 7-dien-1-yl) -2,5,7, 8-tetramethyl-2H-chromen-6-ol
4-hydroxy-2, 3, 6-trimethyl-5- ((6E) -3,7, 11-trimethyldodeca-2, 6, 10-trien-1-yl) phenylacetate (2.0 g,4.74 mmol) was mixed with 50mL diethyl ether and cooled to 5 ℃. Lithium aluminum hydride (2M in THF) (2.96 ml,5.92 mmol) was then added and the reaction stopped by adding 40mL 4N HCl after 3.5 hours at 0-24 ℃. The organic phase was washed once with 40mL of brine and 0.2g of sodium dithionite, then with MgSO 4 And (5) drying. After filtration and evaporation, 2,3, 5-trimethyl-6- ((6E) -3,7, 11-trimethyldodeca-2, 6, 10-trien-1-yl) benzene-1, 4-diol was isolated in 85% yield.
2,3, 5-trimethyl-6- ((6E) -3,7, 11-trimethyldodeca-2, 6, 10-trien-1-yl) benzene-1, 4-diol was dissolved in diethyl ether (7.5 mL), 1.5 equivalents of silver oxide and 46. Mu.L of acetic acid were added, and the mixture was stirred at room temperature for 2 hours. After filtration and purification by chromatography (neutral silica gel), 2,3, 5-trimethyl-6- ((6E) -3,7, 11-trimethyldodeca-2, 6, 10-trien-1-yl) cyclohexa-2, 5-diene-1, 4-dione was isolated in 88% yield.
2,3, 5-trimethyl-6- ((6E) -3,7, 11-trimethyldodeca-2, 6, 10-trien-1-yl) cyclohexa-2, 5-dien-1, 4-dione (1.27 g (3.29 mmol)) and 18ml toluene and 0.15ml (0.988 mmol) 1, 8-diazabicyclo [5.4.0] undec-7-ene (=DBU) were added and stirred under reflux (110 ℃) for 20 hours to give (E) -2- (4, 8-dimethylnon-3, 7-dien-1-yl) -2,5,7, 8-tetramethyl-2H-chromen-6-ol in 86.5% yield.
Experiment series 1
Geranylgeranyl trimethoquinone (purity 97%) (0.5 g (1.183 mmol)) and 6ml of toluene were added and stirred under reflux (110 ℃) for the reaction time shown in table 1 with the corresponding amount of basic catalyst given in table 1 to give 2,5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) -2H-chromen-6-ol (3, 4-dehydro-alpha-tocotrienol) with the conversion and yield shown in table 1.
TABLE 1 different basic catalysts
1 Dmap=4- (dimethylamino) pyridine; dbu=1, 8-diazabicyclo [5.4.0]Undec-7-ene; tea=triethanolamine
2 H.Ripin；D.A.Evans(2002)."pka’s of Nitrogen Acids".
https://organicchemistrydata.org/hansreich/resources/pka/pka_data/ evans_pKa_table.pdf
3 https://www.aatbio.com/data-sets/pka-and-pkb-reference-table
4 n.a. =inapplicable
The results in Table 1 show that all bases used in catalytic amounts are capable of forming the desired product, i.e., 3, 4-dehydro-alpha-tocotrienol. Most of the examples show that very high conversions and yields exceeding 94% can be obtained. In addition, examples 7,8 and 9 in Table 1 show the pK of its conjugate acid a Specific basic catalysts below 8.6 can result in lower conversions and yields. Experiments have also shown that the conversion of pyridine at catalytic concentrations is particularly low. Comparison of example 2 and example 3 shows that extremely high conversions and yields can be obtained despite a ten-fold decrease in catalyst concentration.
Partial hydrogenation
The 3, 4-dehydro-alpha-tocotrienol prepared above (=2, 5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) -2H-chromen-6-ol) was quantitatively hydrogenated to alpha-tocotrienol (=2, 5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) chromen-6-ol) as characterized by nuclear magnetic resonance according to the procedure disclosed in Schudel, mayer, isler, helv.chim. Acta 46,2517-2526 (1963) at page 2524, last paragraph.
Complete hydrogenation
According to Kabbe and Heitzer, synthesis 1978; the final stage of page 888 of 12,888-889, the 3, 4-dehydro- α -tocotrienol (=2, 5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) -2H-chromen-6-ol) prepared above was quantitatively hydrogenated to α -tocopherol (=2, 5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridecyl) -chroman-6-ol), which was characterized by nuclear magnetic resonance.
Experiment series 2
In another series, 0.46g (1.098 mmol) of geranylgeranyl trimethoquinone (purity 97%) and the amount of toluene shown in Table 2 and 5.49. Mu. Mol of DBU (1/200) were added and stirred at reflux (110 ℃) for 24 hours to give 2,5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) -2H-chromen-6-ol (3, 4-dehydro-alpha-tocotrienol), the conversion and yield being shown in Table 2.
Table 2. Using DBU as a base, various concentrations of quinone in toluene (geranylgeranyl trimethoquinone) were used for the ring closure reaction.
Experiment series 3
In another series, 0.46g (1.098 mmol) of geranylgeranyl trimethylbenzoquinone (purity 97%) and 6ml of toluene were added in the presence of 3.5mg of tetrabutylammonium bromide (1 mol% (relative to geranylgeranyl trimethylbenzoquinone)) and 4.7mg of ground solid NaOH (0.1098 mmol,10mol% (relative to geranylgeranyl trimethylbenzoquinone)) were stirred at reflux (110 ℃ C.), the reaction times were as shown in Table 2, yielding 2,5,7, 8-tetramethyl-2- (4, 8, 12-trimethyltridec-3, 7, 11-trien-1-yl) -2H-chromen-6-ol (3, 4-dehydroα -tocotrienol), the conversion and the yield were as shown in Table 3.
Table 3. Solid NaOH was used as basic catalyst.

Claims (15)

1. A process for the preparation of a compound of formula (I),
the process comprising the step of ring closure of a compound of formula (II) in the presence of a basic catalyst to produce a compound of formula (I),
wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl;
R 3 and R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z-configuration or E-configuration when attached to a carbon-carbon double bond,
characterized in that the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.
2. The method according to claim 1, wherein R 1 ＝R 3 ＝R 4 ＝CH 3 。
3. The process according to claim 1 or 2, characterized in that the basic catalyst is either an organic amine, preferably an organic tertiary amine, or a metal hydroxide or carbonate, in particular an organic tertiary amine or an alkali metal hydroxide.
4. The method according to any of the preceding claims, characterized in that the conjugate acid of the basic catalyst has a pK measured in water a The value is between 8.6 and 15.7, in particular between 9 and 15.7.
5. The process according to any of the preceding claims, characterized in that the basic catalyst is selected from 4-dimethylaminopyridine (=dmap), 1, 8-diazabicyclo [5.4.0] undec-7-ene (=dbu), 1, 5-diazabicyclo [4.3.0] non-5-ene (=dbn), 1, 4-diazabicyclo [2.2.2] octane (=dabco), 1-azabicyclo [2.2.2] octane (=quinuclidine) and cytidine, in particular from 4-dimethylaminopyridine (=dmap), 1, 8-diazabicyclo [5.4.0] undec-7-ene (=dbu) and 1-azabicyclo [2.2.2] octane (=quinuclidine).
6. The method according to any of the preceding claims, wherein the compound of formula (I) is a compound of formula (I-BB) and the compound of formula (II) is a compound of formula (II-BB)
7. The process according to any of the preceding claims, characterized in that the ring closure step is carried out in a hydrocarbon solvent, in particular toluene.
8. A process for the preparation of a compound of formula (III),
the method comprises the following steps of
a) A compound of formula (I) prepared according to the process of any one of the preceding claims 1-8,
any of which is provided with a dotted lineIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond;
b) The compounds of formula (I) are partially hydrogenated by means of a hydrogenating agent suitable for partial hydrogenation to give compounds of formula (III).
9. A process for the preparation of a compound of formula (IV),
the method comprises the following steps of
a) A compound of formula (I) prepared according to the process of any one of the preceding claims 1-8,
any of which is provided with a dotted lineIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond;
b') hydrogenating the compound of the formula (I) with the aid of a hydrogenating agent to give the compound of the formula (IV).
10. A composition, the composition comprising:
i) A compound of formula (II)
Wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl;
R 3 and R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond;
and
ii) a basic catalyst;
characterized in that the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.
11. Composition according to any one of the preceding claims, characterized in that the conjugate acid of the basic catalyst has a pK measured in water a The value is between 8.5 and 15.7, in particular between 9 and 15.7.
12. The composition according to any one of claims 10 to 11, wherein the compound of formula (II) is a compound of formula (II-BB)
13. The catalytic use of a base for the ring closure of a compound of formula (II) to produce a compound of formula (I),
wherein the method comprises the steps of
n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;
R 1 represents hydrogen or methyl;
R 3 and R is 4
Or independently of one another represents hydrogen or methyl or methoxy
Or together represent-CH-and form an aromatic group;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond.
14. The use of compounds of the formulSup>A (I-A) or (I-C) or (III-A) or (III-C) or (IV-A) or (IV-C) as antioxidants,
wherein n=0-9, in particular n=8
Wherein n=0 to 12
Wherein n=0-9, in particular n=8
Wherein n=0 to 12
Wherein n=0-9, in particular n=8
Wherein the method comprises the steps of
R 1 Represents hydrogen or methyl;
any with broken linesIndependently of each other, represents a carbon-carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and are in the Z configuration or E configuration when connected to a carbon-carbon double bond.
15. Compounds of formula (I-As) or (I-Cis) or (III-Cis) or (IV-Cs)
Wherein n=3-9, in particular n=8
Wherein n=1-12, in particular n=2-5;
wherein n=3-6, in particular n=5;
wherein n=3-12, in particular n=3-5; (IV-Cs) therein
R 1 Represents hydrogen or methyl;
any with broken linesIndependently of one another, represents carbon-
A carbon single bond or a carbon-carbon double bond; and
any wavy lines represent carbon-carbon bonds independently of each other and when
In the Z configuration or E configuration when attached to a carbon-carbon double bond.
CN202280030782.6A 2021-04-28 2022-04-26 Ring closure of benzoquinone containing unsaturated side chains Using basic catalyst Pending CN117597335A (en)

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GB870638A (en) * 1958-11-07 1961-06-14 Hoffmann La Roche Derivatives of 2,3-dimethoxy-5-methyl benzohydroquinone-(1,4) and a process for the manufacture thereof
GB947643A (en) * 1959-05-25 1964-01-22 Merck & Co Inc Substituted chroman compounds
GB877960A (en) * 1959-07-15 1961-09-20 Hoffmann La Roche The manufacture of pyran derivatives
US3064012A (en) * 1960-07-20 1962-11-13 Merck & Co Inc Derivatives of coenzyme q10
US3154565A (en) * 1962-03-22 1964-10-27 Merck & Co Inc Chromenyl compounds and method of preparing
JPH05156247A (en) * 1991-12-06 1993-06-22 Nippon Suisan Kaisha Ltd New benzopyrane derivative
ATE411307T1 (en) * 2003-12-05 2008-10-15 Dsm Ip Assets Bv METHOD FOR PRODUCING ALKENYLATED HYDROXYLATED AROMATIC COMPOUNDS, CHROME COMPOUNDS AND THEIR ACYLATED DERIVATIVES
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